Mitral regurgitation (MR) imposes a volume overload on the left ventricle which eventually leads to left ventricular dysfunction. Such dysfunction is associated with subsequent morbidity and increased operative mortality. In the initial funding period, we developed a closed-chest chordal rupture model of severe MR, the consequence of which was inevitable left ventricular dysfunction. Thus, we have developed a tool to examine the causes of left ventricular dysfunction in MR. Using this tool: 1) We found that in vivo left ventricular dysfunction correlated closely with the dysfunction of myocytes isolated from the affected ventricle which in turn correlated with the loss of myocyte myofibrils. 2) Excitingly, we found that both the myocyte and ventricular dysfunction were reversible if the regurgitation was corrected by mitral valve replacement. Having defined that left ventricular dysfunction in MR was a reversible property of the myocyte due to myofibrillar loss, we then sought specific mechanisms by which the cell dysfunction occurred. Pilot studies which form the basis of this proposal demonstrated that beta-blockade in MR resulted in striking improvement of both the left ventricular dysfunction and myocyte dysfunction with a return of myofibrillar density toward normal levels. These data suggest that beta-adrenergic overstimulation is one cause of the ventricular dysfunction in experimental MR. In the current proposal, we will complete these pilot studies and cement this premise. Once this is established, we will then address three specific mechanisms by which beta-adrenergic overstimulation could be causing the dysfunction: 1) That tachycardia which occurs with dysfunction and is reduced with beta-blockade is or is not the cause of the negative effects of beta overstimulation and the positive effects of beta-blockade. 2) That although beta-receptor up-regulation occurs with beta-blockade and may be important in the left ventricular response to stress, the primary mechanism by which contractile function is improved by beta-blockade is enhanced innate contractile function. We will test this hypothesis by examining changes in isolated myocyte contractile function in a preparation devoid of adrenergic stimulation. 3) We will determine whether the increased myofibrillar density which must be in part responsible for the improvement seen following a beta- adrenergic blockade is due to a beta-blocker-induced increase in protein synthesis or a decrease in protein degradation.